Ascorbic acid derivative and use as antioxidant

ABSTRACT

This invention relates to a novel ascorbic acid derivative having excellent antioxidant action and a process for preparing the same. 
     Furthermore, this invention also relates to a novel antioxidant comprising the aforementioned ascorbic acid derivative or other known ascorbic acid derivatives.

This is a division of application Ser. No. 07/382,270, filed Jul. 20,1989, U.S. Pat. No. 5,061,812.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

This invention relates to an ascorbic acid derivative, a process forpreparing the same and an antioxidant comprising an ascorbic acidderivative.

(2) Prior Art

Ascorbic acid has antioxidant action and is used for the purpose ofpreventing browing of foods, retaining flavor or freshness of foods orthe like.

Ascorbic acid, however, is susceptible to decomposition and sometimeshard to produce the above-mentioned effects over a long period.

SUMMARY OF THE INVENTION

It is, therefore, a first object of this invention to provide a novelascorbic acid derivative eliminating the aforementioned disadvantages ofthe ascorbic acid. It is a second object of this invention to provide aprocess for preparing the aforesaid novel ascorbic acid derivative. Itis further a third object of this invention to provide an antioxidantcomprising an ascorbic acid derivative.

The first object of this invention has been achieved by an ascorbic acidderivative represented by the general formula (Ia): ##STR1## wherein R₁is a group selected from the group consisting of a heterocyclicring-containing alkyl group, an alkylcarbonylalkyl group, anarylcarbonylalkyl group and an alkoxycarbonylalkyl group containing theterminal alkoxy group having at least 7 carbon atoms.

The second object of this invention has been accomplished by a processfor preparing an ascorbic acid derivative represented by the generalformula (Ia): ##STR2## wherein R₁ is a group selected from the groupconsisting of a heterocyclic ring-containing alkyl group, analkylcarbonylalkyl group, an arylcarbonylalkyl group and analkoxycarbonylalkyl group containing the terminal alkoxy group having atleast 7 carbon atoms, comprising treating a compound represented by thegeneral formula (II): ##STR3## wherein R₁ has the same significance asabove, with an acid to cleave the dioxolane ring in said compound andform a vic-glycol group.

Furthermore, the third object of this invention has been achieved by anantioxidant comprising an ascorbic acid derivative represented by thegeneral formula (IA): ##STR4## wherein R₂ is a group selected from thegroup consisting of a heterocyclic ring-containing alkyl group, analkylcarbonylalkyl group, an arylcarbonylalkyl group, analkoxycarbonylalkyl group, an alkyl group, an aralkyl group and ahydroxycarbonylalkyl group.

The group R₁ in the general formula (Ia) representing the novel ascorbicacid derivative of this invention is different in the number ofsubstituent groups defined therein from the group R₂ in the generalformula (IA) representing the ascorbic acid derivative constituting theantioxidant of this invention. Although the group R₁ has foursubstituent groups, R₂ has the total seven substituent groups includingthe four. The alkoxycarbonylalkyl groups in the group R₁ in the generalformula (Ia) are restricted to those containing the terminal alkoxygroup having at least 7 carbon atoms, whereas such restriction is notplaced on the alkoxycarbonylalkyl groups in the group R₂ in the generalformula (IA). This means that ascorbic acid derivatives excluded fromthe general formula (Ia) defining the novel ascorbic acid derivative canalso be used as the antioxidant of this invention.

The novel ascorbic acid derivative of this invention is initiallyexplained hereinafter.

The novel ascorbic acid derivative of this invention is represented bythe general formula (Ia): ##STR5## wherein R₁ is a group selected fromthe group consisting of a heterocyclic ring-containing alkyl group, analkylcarbonylalkyl group, an arylcarbonylalkyl group and analkoxycarbonylalkyl group containing the terminal alkoxy group having atleast 7 carbon atoms.

Heterocyclic ring containing alkyl groups having 1 to 3 nitrogen atomsin the ring are herein preferred as the heterocyclic ring-containingalkyl groups, and examples thereof include groups represented by thegeneral formulae: ##STR6## wherein R₃ is an alkylene group which mayoptionally have a branched chain. Particularly preferred heterocyclicring-containing alkyl groups are pyridylmethyl group, pyrimidylmethylgroup, triazylmethyl group and the like.

Examples of the alkylcarbonylalkyl groups include groups represented bythe general formula. ##STR7## wherein R₄ is an alkylene group which mayoptionally have a branched chain; R₅ is an alkyl group which mayoptionally have a branched chain. Particularly preferredalkylcarbonylalkyl groups are ##STR8## and the like.

Furthermore, examples of the arylcarbonylalkyl groups include groupsrepresented by the general formula: ##STR9## wherein R₆ is an alkylenegroup which may optionally have a branched chain; Ar is an aryl groupwhich may optionally have a substituent group on the ring. Particularlypreferred arylcarbonylalkyl groups are --CH₂ --CO--C₆ H₅ and the like.

Examples of the alkoxycarbonylalkyl groups containing the terminalalkoxy group having at least 7 carbon atoms include groups representedby the general formula: ##STR10## wherein R₇ is an alkylene group whichmay optionally have a branched chain; R₈ is an alkyl group of 7 or morecarbon atoms which may optionally have a branched chain. Particularlypreferred alkoxycarbonylalkyl groups are --CH₂ --CO--O--n--C₁₀ H₂₁ andthe like.

The novel ascorbic acid derivative of this invention has excellentantioxidant action and can be preferably used as food antioxidants orbeautifying and whitening cosmetics.

The process for preparing the novel ascorbic acid derivative representedby the above-mentioned general formula (Ia) of this invention isexplained hereinafter.

In the process of this invention, a compound represented by the generalformula (II): ##STR11## wherein R₁ is a group selected from the groupconsisting of a heterocyclic ring-containing alkyl group, analkylcarbonylalkyl group, an arylcarbonylalkyl group and analkoxycarbonylalkyl group containing the terminal alkoxy group having atleast 7 carbon atoms, is used as a starting material.

Such a compound represented by the formula (II) is obtained byketalizing ascorbic acid according to a conventional method to provide5,6-O-isopropylideneascorbic acid represented by the formula (III):##STR12## and further reacting the resulting compound (III) with anorganic halide represented by the general formula: R₁ X wherein R₁ isthe same as the group R₁ in the general formula (II); X is a halogenatom, to etherify the hydroxyl group at the 3-position of the compound(III). This dehydrohalogenation may be carried out either according tothe Williamson reaction or in an organic phase-aqueous phase systemusing a phase transfer catalyst.

According to the process of this invention, the compound (II) as astarting material is treated with an acid to cleave the dioxolane ringin the above-mentioned compound to form a vic-glycol group. Thereby thedesired ascorbic acid derivative represented by the general formula (Ia)is obtained.

Example of the acid used for the reaction include hydrochloric acid,acetic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonicacid, camphorsulfonic acid and the like. The reaction is preferablycarried out in at least one organic solvents selected from methanol,ethanol, dioxane, tetrahydrofuran and 1,2-dimethoxyethane.

The antioxidant of this invention is explained hereinafter.

As explained above, the antioxidant of this invention comprises theascorbic acid derivative represented by the general formula (IA):##STR13## The group R₂ in the formula is within a wider scope than thegroup R₁ in the general formula (Ia) representing the novel ascorbicacid derivative as described above, and therefore the ascorbic acidderivative represented by the general formula (IA) includes also knowncompounds.

Thus, the group R₂ includes four substituent groups (heterocyclicring-containing alkyl group, alkylcarbonylalkyl group, arylcarbonylalkylgroup and alkoxycarbonylalkyl group) similar to the group R₁, besidesthose, further three substituent groups of alkyl group, aralkyl groupand hydroxycarbonylalkyl group. The term "alkyl" in the aforesaidsubstituent groups means a straight or branched alkyl group. Thealkoxycarbonylalkyl groups in the group R₁ in the general formula (Ia)are restricted to those containing the terminal alkoxy group having atleast 7 carbon atoms; however, the group R₂ in the general formula (IA)includes a wide scope of alkoxycarbonylalkyl groups without suchrestriction thereon.

Such an ascorbic acid derivative represented by the general formula (IA)has the ability to eliminate radicals and is preferably used as anantioxidant with advantages in better stability than that of ascorbicacid and conventional ascorbic acid derivatives.

EXAMPLES

Examples of this invention are explained hereinafter.

PREPARATION EXAMPLE 1 [PREPARATION OF NOVEL ASCORBIC ACID DERIVATIVE(IA)] (1) Synthesis of L-5,6-O-isopropylideneascorbic acid

Ascorbic acid in an amount of 180 g was stirred in 750 ml of acetone andwarmed to 40° C. Acetyl chloride in a volume of 20 ml was added, andstirring was continued to form a slurry layer.

After 3 hours, the slurry layer was cooled with ice to collect depositedprecipitates by filtration. The resulting precipitates were washed witha mixture of cold acetone-n-hexane (3:7) on a funnel and dried withsilica gel under reduced pressure.

Recrystallization from acetone was then carried out to provide 190 g ofL-5,6-O-isopropylidene ascorbic acid (melting point: 206 °-208° C.).

(2) Synthesis of L-5,6-O-isopropylidene-3-O-benzoylmethylascorbic acid

In 30 ml of DMSO, was dissolved 4.32 g of the compound obtained in (1).After NaHCO3 in an amount of 1.78 g was added, the resulting solutionwas stirred at room temperature for 30 minutes. To the solution, wasadded 4.37 g of phenacyl bromide, and the obtained solution was warmedto 40° C. and stirred for 18 hours. After cooling, 80 ml of H₂ O wasadded, and pH was adjusted to 5 with 4 N hydrochloric acid. ThepH-adjusted solution was shaken with ethyl acetate (100 ml×2). Organiclayers were combined, washed with water and saturated aqueous sodiumchloride, dried over sodium sulfate and concentrated under reducedpressure. The resulting oily substance was subjected to silica gelcolumn chromatography and eluted with a mixture of benzene-ethyl acetateto provide a L-5,6-O-isopropylidene-3-O-benzoylmethylascorbic acid.

(3) Synthesis of L-3-O-benzoylmethylascorbic acid

In 40 ml of a mixture of tetrahydrofuranmethanol (3:1), was dissolved3.3 g of the compound obtained in (2), and 10 ml of 2 N hydrochloricacid was added to stir the resulting solution at room temperature for 20hours. The reaction solution was concentrated under reduced pressure,and the residue was recrystallized from ethyl acetate-petroleum ether toafford L-3-O-benzoylmethylascorbic acid (corresponding to compound No.112 in Table-1).

The resulting compound No. 112 of this invention was used forantioxidant tests described below.

PREPARATION EXAMPLE 2 [Preparation of Novel Ascorbic Acid Derivative]

Procedures were followed in the same manner as in Preparation example 1to provide novel compound Nos. 110 and 115 shown in Table-1 mentionedbelow.

Such compounds were used for the antioxidant tests described below.

PREPARATION EXAMPLE 3 [Preparation of Novel Ascorbic Acid Derivative](1) Synthesis of L-5,6-isopropylidene-3-O-(3-picoyl) ascorbic acid

In 40 ml of distilled water, was dissolved 1.66 g of NaHCO₃, and 80 mlof methyl ethyl ketone was added. To the resulting solution, was added4.32 g of the L-5,6-O-isopropylideneascorbic acid obtained in (1) ofPreparation example 1. The obtained mixture was stirred, and 3.26 g of3-picoyl chloride, 1.66 g of NaHCO₃ and 1.60 g of tetrabutylammoniumbromide were added thereto. The resulting mixture was heated to 70° C.and vigorously stirred for 10 hours. The organic layer was separated,and the aqueous layer was adjusted to pH 4 with 4 N hydrochloric acidand shaken with 100 ml of ethyl acetate. Organic layers were combined,washed with water, dried over sodium sulfate and concentrated underreduced pressure. The resulting residue was subjected to silica gelcolumn chromatography and eluted with a mixture of benzene-ethyl acetateto provide L-5,6-isopropylidene-3-O-(3-picoyl)ascorbic acid.

(2) Synthesis of L-3-O-(3-Picoyl) Ascorbic Acid

Operations were performed in the same manner as in (3) of Preparationexample 1, except that the compound obtained in (1) was used.Recrystallization from benzene-petroleum ether was carried out toprovide L-3-O-(3-picoyl)ascorbic acid (corresponding to compound No. 113in Table-1).

The obtained compound No. 113 of this invention was used for theantioxidant tests mentioned below.

PREPARATION REFERENTIAL EXAMPLE 1 [Preparation of Other Ascorbic AcidDerivatives]

Procedures were followed in the same manner as in Preparation example 1to provide compound Nos. 101, 102, 103, 104, 105, 106, 107, 108, 109,111 and 114 indicated in Table-1 mentioned below.

The resulting compounds were also used for the antioxidant testsdescribed below.

                                      TABLE 1                                     __________________________________________________________________________    Compound                                                                      No.   R.sub.1     mp    NMR δ value                                     __________________________________________________________________________    101   (CH.sub.2).sub.17 CH.sub.3                                                                103° C.                                                                      0.85(3H, m)1.24(32H, m)3.45(3H, m)                                            4.36(2H, t)4.73(H, s)                                 102   (CH.sub.2).sub.11 CH.sub.3                                                                86-88° C.                                                                    0.85(3H, m)1.25(20H, m)3.35(3H, m)                                            4.36(2H, t)4.73(H, s)                                 103   (CH.sub.2).sub.7 CH.sub.3                                                                 58-61° C.                                                                    0.86(3H, m)1.27(12H, m)3.50(3H, m)                                            4.36(2H, t)4.73(H, s)                                 104   (CH.sub.2).sub.3 CH.sub.3                                                                 Oily  0.94(3H, m)1.60(4H, m)3.71(3H, m)                                       substance                                                                           4.48(2H, t)4.79(H, d, 1Hz)                            105   (CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                       Oily  1.21(3H, t)1.76(4H, m)2.36(2H, m)                                       substance                                                                           3.70(3H, m)4.09(2H, q)4.49(2H, t)                                             4.79(H, s)                                            106   (CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                       Oily  1.21(3H, t)2.17(2H, m)2.47(2H, t)                                       substance                                                                           3.70(3H, m)4.09(2H, q)4.51(2H, t)                                             4.80(H, s)                                            107   (CH.sub.2).sub.3 COOH                                                                     Oily  2.05(2H,. m)2.48(2H, t)3.70(3H, m)                                      substance                                                                           4.54(2H, t)4.80(H, s)                                 108                                                                                  ##STR14##  141° C.                                                                       1.20(3H, t)1.48(2H, d)3.34(3H, m) 4.15(2H,                                   q)4.81(H, s)5.31(H, q)                                109   CH.sub.2 COO-n-C.sub.4 H.sub.9                                                             81° C.                                                                      0.91(3H, t)1.56(4H, m)3.73(3H, m)                                             4.14(2H, t)4.90(H, d, 2Hz)5.08(2H, s)                 110   CH.sub.2 COO-n-C.sub.10 H.sub.21                                                          Oily  0.88(3H, m)1.25(16H, m)3.70(3H, m)                                      substance                                                                           4.28(2H, t)4.90(H, s)5.09(2H, s)                      111   CH.sub.2 COOC.sub.2 H.sub.5                                                               Oily  1.29(3H, t)3.68(3H, m)4.27(2H, q)                                       substance                                                                           4.87(H, d, 2Hz)5.03(2H, s)                            112                                                                                  ##STR15##   92° C.                                                                      3.44(3H, m)4.92(H, s)5.79(H, d, 7Hz) 7.61(3H,                                 m)7.96(2H, m)                                         113                                                                                  ##STR16##  154-160° C.                                                                  3.69(3H, m)4.85(H, d, 2Hz)5.61(2H, s) 7.50(H,                                 m)8.0(H, m)8.59(2H, m)                                114   (CH.sub.2).sub.10 COOH                                                                     90° C.                                                                      1.32(16H, m)2.29(2H, t)3.61(3H, m)                                            4.48(2H, t)4.78(H, s)                                 115   CH.sub.2 COCH.sub.3                                                                       143° C.                                                                      2.10(3H, s)3.48(3H, m)4.84(H, s)5.01                                          (2H, m)                                               __________________________________________________________________________

TEST EXAMPLE 1 (ANTIOXIDANT ACTION EXAMINED BY USING STABLE RADICALS)

Reduction activity of a,α-diphenyl-β-picrylhydrazyl (DPPH) which was astable free radical was examined according to the M. S. Blois method(Nature, vol. 181, page 1199, 1958) and used as an index to antioxidantaction. Thus, specimens were added to 3 ml of a 0.1 mM DPPH solution inethanol, and absorbance at a wavelength of 517 nm was measured using aspectrophotometer after 20 minutes. The difference in absorbance fromthe solvent control [0.5% or less of dimethylformamide (DMF)] was takenas the reduction activity.

The 50% radical eliminating concentrations for the test compounds areshown in Table-2.

As can be seen from Table-2, the test compounds were found to haveimproved antioxidant action. It has been also clarified that the othercompound Nos. 102 to 115 have better antioxidant ability than thecompound No. 101 wherein R₁ is a long-chain alkyl group.

                  TABLE 2                                                         ______________________________________                                                      50% radical eliminating                                         Compound No.  concentration                                                   ______________________________________                                        101           3.2 × 10.sup.-5 M                                         102           1.8                                                             103           1.9                                                             104           2.3                                                             105           2.0                                                             106           2.1                                                             107           2.7                                                             108           1.9                                                             109           1.8                                                             110           2.3                                                             111           2.2                                                             112           2.3                                                             113           2.3                                                             114           2.4                                                             115           2.2                                                             ______________________________________                                    

As detailed above, this invention provides a novel ascorbic acidderivative having excellent antioxidant action and a process forpreparing the same.

Furthermore, this invention also provides a novel antioxidant comprisingthe aforementioned ascorbic acid derivative or other known ascorbic acidderivatives.

We claim:
 1. An ascorbic acid derivative represented by the formula(Ia): ##STR17## wherein R₁ is selected from the group consisting of aheterocyclic ring-containing an alkyl group.
 2. An ascorbic acidderivative of claim 1, wherein said heterocyclic ring-containing alkylgroup is a heterocyclic ring-containing alkyl group containing 1 to 3nitrogen atoms in the heterocyclic ring.
 3. An ascorbic acid derivativeof claim 2, wherein said heterocyclic ring-containing alkyl group isrepresented by general formula: ##STR18## wherein R₃ represents analkylene group which may optionally have a branched chain.
 4. Anascorbic acid derivative of claim 3, wherein said heterocyclicring-containing alkyl group is selected from the group consisting ofpyridylmethyl, pyrimidylmethyl and triazylmethyl.
 5. An antioxidantcomposition comprising together with a suitable carrier or diluent anascorbic acid derivative represented by the formula (IA): ##STR19##wherein R₂ is a group selected from the group consisting of aheterocyclic ring-containing alkyl group, an alkyl-carbonylalkyl group,an arylcarbonylalkyl group, an alkoxycarbonylalkyl group, an alkylgroup, an aralkyl group and a hydroxycarbonylalkyl group.
 6. Anantioxidant of claim 5, wherein said heterocyclic ring-containing alkylgroup is a heterocyclic ring-containing alkyl group containing 1 to 3nitrogen atoms in the heterocyclic ring.
 7. An antioxidant of claim 6,wherein said heterocyclic ring-containing alkyl group is represented bythe formula: ##STR20## wherein R₃ represents an alkylene group which mayoptionally have a branched chain.
 8. An antioxidant of claim 7, whereinsaid heterocyclic ring-containing alkyl group is selected from the groupconsisting of pyridylmethyl, pyrimidylmethyl and triazylmethyl.
 9. Anantioxidant of claim 5, wherein said alkylcarbonylalkyl group isrepresented by general formula: ##STR21## wherein R₄ represents analkylene group which may optionally have a branched chain and R₅represents an alkyl group which may optionally have a branched chain.10. An antioxidant of claim 9, wherein said alkylcarbonylalkyl group isselected from the group consisting of --CH₂ -CO-CH₃ and --CO₂ -CO-C₂ H₅.11. An antioxidant of claim 5, wherein said arylcarbonylalkyl group isrepresented by general formula: ##STR22## wherein R₆ represents analkylene group which may optionally have a branched chain and Ar is anaryl group which may optionally have a substituent thereon.
 12. Anantioxidant of claim 11, wherein said arylcarbonylalkyl group is --CH₂-C₆ H₅.
 13. An antioxidant of claim 5, wherein said arylcarbonylalkylgroup is represented by the formula: ##STR23## wherein R₇ represents analkylene group which may optionally have a branched chain and R₈ is analkyl group.
 14. An antioxidant of claim 13, wherein R₈ is an alkylgroup which may optionally have a branched chain.
 15. An antioxidant ofclaim 14, wherein said alkoxycarbonylalkyl group is --CH₂ -COO-n-C10H21.16. An antioxidant of claim 5, wherein said alkyl group is a straight orbranched alkyl group.
 17. An antioxidant of claim 5, wherein the alkylmoiety of said hydroxycarbonylalkyl group is a straight or branchedalkyl group.
 18. An antioxidant of claim 5, wherein the alkyl moiety ofsaid aralkyl group is a straight or branched alkyl group.